Arthritis is largely classified into degenerative arthritis (osteoarthritis) and rheumatoid arthritis. Degenerative arthritis, called osteoarthritis, is a disease which is very common and mainly occurs in middle or old age and also which causes pain, stiffness and restriction at the joints to which a high body weight is applied, such as the knee joint and the hip joint. Arthritis, which was simply regarded in the past as a sign of the aging process, is currently considered to have symptoms that vary depending on various factors such as age, inheritance, obesity, shape of joints, hormones, etc. Degenerative arthritis is known to be mainly caused by gradual damage done to the articular cartilage which causes chronic inflammation which is then accompanied by the degeneration of peripheral tissue. Specifically, as physical stress accumulates on the cartilage tissue, transcription factors such as NF-kB and AP-1 are activated in the cartilage tissue, undesirably causing chronic inflammation. When this happens, factors for mediating and amplifying the inflammation, such as COX-2, LOX and the like, are expressed, peripheral blood circulation is suppressed, and tissue degrading factors such as matrix metalloproteinases (MMPs), hyaluronidase, iNOS and the like are over-expressed, thus degenerating the cartilage tissue to thereby affect peripheral tissue such as muscles, tendons, and ligaments, resulting in severe pain.
On the other hand, rheumatoid arthritis is an inflammatory self-immune disease which occurs at multiple joints. The synovial tissue and synovia of the patient suffering from rheumatoid arthritis may cause chronic inflammation by excessive action of inflammatory cells (macrophages, T-cells, B-cells, dendritic cells, etc.), thus damaging the joints and cartilage and inducing pain.
As mentioned above, the tissue affected by degenerative arthritis or rheumatoid arthritis involves chronically elevated levels of inflammatory mediators such as COX, LOX, iNOS and the like, and also involves the overly activated MMP enzymes that decompose the tissue. Conventionally, drugs for suppressing such factors or methods of inhibiting activities of tissue-decomposing enzymes resulting from inflammatory reactions have been used. The current major drugs used to treat degenerative arthritis and rheumatoid arthritis are non-steroidal anti-inflammatory drugs (NSAIDs). These NSAIDs slightly improve the symptoms but cannot block the loss of cartilage around the joint or the progress of the disease, and may cause severe side effects. For these reasons, about a half the patients under treatment using these drugs should discontinue the treatment within one year. The NSAID therapy which suppresses the biochemical processes related with the symptoms rather than with the causes of arthritis is problematic because its side effects outbalance its efficacy.
The upstream factors to the chronic activation of the inflammatory mediators such as COX, LOX, iNOS and the like include NF-kB and AP-1. These transcription factors are underlying and common causes of degenerative and rheumatoid arthritis, and function to obstruct the healing of the damaged tissue by compromising the process for replacing abnormal cells with new cells (Simmonds, R. E. & Foxwell, B. M. Rheumatology Advance Access published Jan. 29, 2008).
The conventional treatments are problematic because they focus only on pain suppression by inhibiting the acute inflammatory reaction and do not fundamentally treat the chronic inflammation and degeneration of tissue. Even in inhibiting the acute inflammation and pain, oral administration of current NSAIDs cause serious side effects such as gastrointestinal bleeding or thrombosis. These problems have led to widespread use of their local application using patch type of products. However, their pain-relieving effects are only temporary and do not significantly contribute to improvement in quality of life of the patients.
Hence, there is a need for the development of drugs which have both safety and fundamental treatment effects for degenerative arthritis and rheumatoid arthritis by inhibiting over-expression of NF-kB and AP-1.